IUGR PREVENTIONי שערי צדקאהמרכז הרפו, אביטןר תהילה "ד

Interventions to prevent IUGR have included:

• Encouraging women to start pregnancy when their Body Mass Index (BMI) isbetween extremes (grade B).

• Avoiding multiple pregnancies (grade A),

• Stabilizing chronic diseases that can influence placenta vascularization

• Stopping smoking as soon as possible (grade A),

• Limiting hypoglycemia during pregnancy (grade C)

• Tolerating maternal hypertension throughout pregnancy.

J Gynecol Obstet Biol Reprod 2013 Dec;42(8): [Prevention of IUGR]. Nizard J

ASPIRIN

CLEXAN

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SILDENAFIL

• While a few of interventions have shown benefit in initial studies, themost consistent and promising prophylaxis, showing modest benefit inrigorous randomized trials, has been low-dose aspirin.

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Given the possibility ofpublication bias exaggeratingthe effect size and theinconsistency in the MFMUtrial, it should be pointed outthat further results couldchange this finding (to asmuch as a 31% reduction inIUGR with aspirin use in high-risk women).

• Prophylaxis with low-dose aspirin beginning after the first trimester of pregnancy is beneficial for perinatal health outcomes in women at elevated risk of preeclampsia.

• Specifically, a modestly reduced risk of preterm birth and IUGR (20% 95% CI, 0.65 to 0.99; k=13; n=12,504; I2=36.9%)

• While available evidence suggests that there is a reduced risk of perinatal mortality, the CI crossed null.

ASPIRIN

• Based on the included trials, no increased risk for abruption or other bleeding-related complications.

• While the evidence on long-term outcomes for offspring from in utero aspirin exposure (low-dose) is limited, follow up data from one large RCT was reassuring.

ASPIRIN - Risks?

• The aspirin dosage used in the trials ranged from 60 to 150 mg daily.

Evaluation of differences in effect by the dose of aspirin using a 75 mg

cut-point revealed only one outcome with a significant difference; the

preterm birth estimate of benefit was greater in studies using a dose

of at least 75 mg.

ASPIRIN - Dosage

• There is some evidence thatpreeclampsia may result from problemswith the process of trophoblasticinvasion completed around 16 weeks ofgestation.

• Thus, initiating treatment before orduring this process has beenrecommended due to the plausiblemechanism of action.

ASPIRIN - Timing

ASPIRIN - TimingASPIRIN - Timing

For women randomized before 16weeks, the relative risk was 0.76, with a95% CI of 0.61-0.94 (13 trials, 6393women).

For women randomized at or after 16weeks, the relative risk was 0.95, with a95% CI of 0.84 to 1.08 (18 trials, 14,996women).

There was no statistically significant difference in treatmenteffect between the 2 subgroups (interaction test, P =0.08;heterogeneity I2, 25%).

ASPIRIN - Timing

ASPIRIN

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Who?

women with acquired

thrombophilias

women with inherited

thrombophilias

Women without Thrombophilia

CLEXAN

• In women with acquired thrombophilias (i.e. lupus anticoagulant, anticardiolipinantibodies and beta-2 glycoprotein I antibodies),

• Prevention of placenta-related adverse pregnancy outcomes (APOs), such aspreeclampsia, fetal growth restriction (FGR), abruption, and fetal death,commonly rests on the administration of low molecular weight heparin (LMWH).

1. American College of Obstetricians and Gynecologists: Antiphospholipid syndrome. Practice Bulletin # 132. Obstet Gynecol 2012;120:1514–21

2. Duhl AJ, Paidas MJ, Ural SH, et al. (Pregnancy and Thrombosis Working Group). Antithrombotic therapy and pregnancy: consensus report and recommendations forprevention and treatment of venous thromboembolism and adverse pregnancy outcomes. Am J Obstet Gynecol 2007;197; 457-e1–21

3. Wu P, Poole TC, Pickett JA, et al. Current obstetric guidelines on thromboprophylaxis in the United Kingdom: evidence based medicine? Eur J Obstet Gynecol ReprodBiol 2013;168(1):7–11.

CLEXAN (1)

• Over the past 20 years, case-control studies have suggested an association

between the risk of placental-implantation related APO and inherited

thrombophilias, including factor V Leiden, prothrombin gene mutation G20210A,

protein S or C deficiency, antithrombin III deficiency, and hyperhomocysteinemia.

CLEXAN (2)

CLEXAN

• In 2013, a Cochrane meta-analysis of RCTs of thromboprophylaxis forAPO related to placental insufficiency.

• The included studies recruited women considered to be at increasedrisk of adverse outcomes from placental insufficiency, pre- dominantlybased on a past history (particularly pre-eclampsia, eclampsia, renaldisease, fetal growth restriction, or fetal death).

• They concluded that the risk of preterm preeclampsia (RR = 0.23) andpreterm birth weight less than the tenth centile (RR = 0.35) wassignificantly decreased by prophylaxis.

CLEXAN (3)

Antithrombotic therapy for improving maternal or infant health outcomes in women considered at risk of placental dysfunction

Cochrane Database of Systematic Reviews24 JUL 2013 DOI: 10.1002/14651858.CD006780.pub3http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD006780.pub3/full#CD006780-fig-00112

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• Metaanalysis has evaluated the published RCTs comparing LMWH versus noLMWH for the prevention of recurrent placenta mediated APOs in the absence ofantiphospholipid antibodies.

• The metaanalysis found that LMWH significantly reduced the occurrence of anyplacenta-mediated APOs [preeclampsia, abruption, SGA less than the tenthcentile, or pregnancy loss >20 weeks; RR = 0.52, 95% confidence interval (CI) 0.32–0.86] and even more the occurrence of severe APOs (severe or early onsetpreeclampsia, abruption, SGA less than the fifth centile, or pregnancy loss >20weeks; RR = 0.39, 95% CI 0.23–0.55).

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• The results of the remaining published RCTs on the use of LMWH for the prevention of APOs among women without inherited thrombophilias.

CLEXAN

• The cumulative results confirm that LMWH significantly lowers therecurrence of APOs as a result of placental insufficiency compared with noLMWH (43/351vs 100/351, RR = 0.43, 95% CI 0.30–0.60).

• The number needed to treat (NNT) to prevent one APO is 6 (95% CI: 4–10).

• The benefit of LMWH is particularly strong for cases of severe

and preterm APOs, which have a higher probability of an

underlying placenta vascular disease or abnormal placentation

than mild APOs or those occurring at term.

• Thus, the more strongest the criteria for the definition of APO,

the more likely the APO is indeed placenta related, at high risk for

recurrence, and more likely to benefit from LMWH prophylaxis.

CLEXAN - Conclusion

Ideal candidates for LMWH prophylaxis would be:

• women with a history of prior severe or catastrophic adverse obstetric outcomes with pathologicevidence of lesions as a result of abnormal placentation.

• In the absence of placental histology, the probability that abnormal placentation was involvedincreases with the severity of the clinical manifestation (for example, more likely with FGR belowthe third centile that above the fifth centile) and with the number of adverse outcomes occurringin association (for example, severe preeclampsia with FGR, placental abruption, or stillbirth).

• Moreover, the lower the gestational age at delivery, the more likely the adverse outcome wasindeed related to abnormal placentation.

CLEXAN - Conclusion

CLEXAN + ASPIRIN

CLEXAN + ASPIRIN

The findings of this systematic review and meta-analysis suggest that, in women who developed

PE in a previous pregnancy, the combination of LMWH and low-dose aspirin started in early

pregnancy is superior to low-dose aspirin alone for the prevention of early-onset PE and the

delivery of a SGA neonate.

CLEXAN + ASPIRIN

• In women receiving low-dose aspirin for a history of severe preeclampsia

before 34 weeks of gestation, the administration of a daily prophylactic dose

of enoxaparin in the antepartum period does not significantly reduce placenta

mediated complications.

ASPIRIN

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Pravastatin was shown in various preclinical and clinical studies to

(1) reverse the pregnancy-specific angiogenic imbalance associatedwith preeclampsia,

(2) restore global endothelial health,

(3) prevent oxidative and inflammatory injury

PRAVASTATIN

• Despite its category X classification, pravastatin has not been shownto be teratogenic in animal and human cohort studies.

• Based on these, the NIH Network started a double blinded placebocontrolled pilot trial to collect preliminary maternal-fetal safety datafor pravastatin during pregnancy (ClinicalTrials.gov IdentifierNCT01717586).

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• Pilot randomized trial designed to determine pravastatin safety and pharmacokinetics in pregnant women at high risk of PE. (History of severe preeclampsia in a prior pregnancy that required delivery prior to 34 weeks’ gestation.)

• No identifiable safety risks associated with pravastatin use.

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There were no differencesbetween the 2 groups inrates of study drug sideeffects, congenitalanomalies, or otheradverse or serious adverseevents.There was no maternal,fetal, or neonatal death.

Four subjects in the placebogroup developedpreeclampsia compared withnone in the pravastatingroup.Pravastatin use wasassociated with a morefavorable pregnancyangiogenic profile.

• A recent landmark study did not find congenital malformations and organ-specific malformations in the offspring of over 800,000 women exposed to statins during the first trimester of pregnancy.

PRAVASTATIN

Bateman BT, et al. Statins and congenital malformations: cohort study. BMJ. 2015;350:h1035.

Bateman BT, et al. Statins and congenital malformations: cohort study. BMJ. 2015;350:h1035.

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CLEXAN

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SILDENAFIL

• Following data from rat and pig models of IUGR, it was determined that myometrialsmall artery function was aberrant in IUGR (increased contraction/ reducedvasodilatation).

• Incubation with Sildenafil citrate reversed the increase in contraction and improvedsignificantly vasodilatation in arteries from pregnancies complicated by IUGR.

• They postulated that Sildenafil citrate may offer a potential therapeutic strategy toimprove uteroplacental blood flow in IUGR pregnancies.

* Wareing M, Myers JE, O’Hara M, Baker PN. Sildenafil citrate (Viagra) enhances vasodilatation in fetal growth restriction. J Clin

Endocrinol Metab 2005;90:2550–5.

SILDENAFIL - hypothesis

• Women were offered Sildenafil if their pregnancy was complicated by severe early-onset IUGR (ultrasound estimation of the fetal AC of <5th percentile) with an estimated probability of ‘intact’ survival of <50%.

• Excluding known aneuploidy, anomaly, syndrome or congenital infection, or if there was a plan to terminate the pregnancy.

• Matching criteria were as follows: (i) maternal age (±5 years); (ii) gestational age at eligibility (±14 days); (iii) parity (0, 1, ‡2); and (iv) eligibility to be offered Sildenafil.

SILDENAFIL

• Other than Sildenafil therapy, management was similar between the two groups.

• Fetal surveillance occurred at least as frequently as every 6–8 days for

outpatients and at least twice weekly for inpatients.

• Women in the Sildenafil-treated group were also monitored for adverse side-

effects, such as flushing, lightheadedness and visual disturbance.

SILDENAFIL

• The primary outcome for this analysis was the proportion of women in each group for whom fetal

AC growth velocity increased post-eligibility.

• Fetal growth velocity was defined as the average daily increase in ultrasound-estimated AC.

• The measurements of AC were performed by standardised ultrasound technique and repeated at

least four times per scan, with the average AC reported in an effort to reduce inter-observer

variability.

• Thus, if the interval between scans was 18 days, and the actual AC increased by the equivalent of

9 days (in millimetres), the average daily growth was deemed to be 0.5.

SILDENAFIL

• Other than one stillbirth within 48 hours of commencing Sildenafil treatment, Sildenafil

treatment was associated with increased post-eligibility fetal AC growth velocity [9/10

(treated) versus 7/17 (naive); odds ratio, 12.9 (95% CI, 1.3, 126)]

• Both survival to, and intact survival at, hospital discharge tended to be more frequent in

the fetuses/neonates exposed to Sildenafil in utero, but we were underpowered to

identify or to exclude a significant difference in these outcomes.

SILDENAFIL

• This is the first study to assess the potential benefit of Sildenafil therapy targetedto improve perinatal outcomes in pregnancies complicated by severe early-onsetIUGR.

• It is also reassuring that there were no adverse maternal side-effects fromSildenafil therapy in the study group.

SILDENAFIL

ASPIRIN

CLEXAN

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ASPIRIN

In the absence of official recommendations, ideal candidates for LMWH prophylaxis would be:

• women with a history of prior severe or catastrophic adverse obstetric outcomes with pathologicevidence of lesions as a result of abnormal placentation.

• In the absence of placental histology, the probability that abnormal placentation was involvedincreases with the severity of the clinical manifestation (for example, more likely with FGR belowthe third centile that above the fifth centile) and with the number of adverse outcomes occurringin association (for example, severe preeclampsia with FGR, placental abruption, or stillbirth).

• Moreover, the lower the gestational age at delivery, the more likely the adverse outcome wasindeed related to abnormal placentation.

CLEXAN - Conclusion

• Pravastatin has been shown in preclinical

studies to reverse various pathophysiological

pathways associated with preeclampsia,

providing biological plausibility for its use for

preeclampsia prevention.

PRAVASTATIN

• Potential benefit of Sildenafil therapy targeted to improve perinatal outcomes in

pregnancies complicated by severe early-onset IUGR.

• Randomised controlled trial data are required to determine whether Sildenafil

improves perinatal outcomes.

SILDENAFIL